Submissions for variant NM_000051.4(ATM):c.2200_2204dup (p.Ile735delinsMetTer)

dbSNP: rs1555074976

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480351	SCV000570328	likely pathogenic	not provided	2016-05-13	criteria provided, single submitter	clinical testing	This duplication of 5 nucleotides in ATM is denoted c.2200_2204dupGTAAT at the cDNA level and p.Ile735MetfsX2 (I735MfsX2) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GGGT[GTAAT]AGCT. The duplication causes a frameshift which changes an Isoleucine to a Methionine at codon 735 and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307517	SCV002600387	likely pathogenic	Malignant tumor of breast	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2200_2204dupGTAAT (p.Ile735MetfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251210 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2200_2204dupGTAAT in individuals affected with ATM-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525863	SCV003344374	pathogenic	Ataxia-telangiectasia syndrome	2022-04-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 421206). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile735Metfs*2) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872).
Baylor Genetics	RCV003464017	SCV004213920	likely pathogenic	Familial cancer of breast	2022-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003464017	SCV004933655	pathogenic	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.